Neurodegenerative diseases (NDDs), which have no known cures and elusive causes, result in irreversible damage to the brain and nervous system. Research into these diseases typically focuses on the brain, but mouse studies from the last few years suggest that the microbiome plays a role in the onset and progression of some NDDs, as well. At ASM Microbe, the annual meeting of the American Society for Microbiology, researchers reported a new link in humans between a metabolite produced by gut microbes and three neurodegenerative diseases. Their analysis suggests that the metabolite DHPS (2,3-dihydroxypropane-1-sulfonate) may help answer critical questions about how sulfur metabolism can connect the microbiome to these diseases. DHPS is one of the most abundant organic sulfur compounds in the biosphere. DHPS can be derived from the microbial degradation of sulfoquinovose, a ubiquitous compound in photosynthetic organisms.
DHPS derived from dietary intake could be transformed into sulfide by intestinal microbiota and thus impacts human health. DHPS has not previously been detected in people, and the researchers noted that metabolites produced by gut microbes in patients with NDDs might offer valuable clues to a better understanding, which could lead to improved diagnostic tools or even treatments. With the rising incidence of inflammatory bowel diseases, there has been an increasing concern that dietary DHPS could be converted by intestinal microbiota into sulfide, which could serve as a pathogeny of intestinal inflammation and colorectal cancer. In previous studies, researchers have found that fecal transplants can alleviate Alzheimer’s disease-like progression in mouse models, and when fecal transplants from people with the disease are administered to mice, the animals experience impairments in memory function.
The researchers undertook the new study to identify distinct bacterial and metabolite profiles of the gut microbiome in people diagnosed with 1 of 3 NDDs: Alzheimer’s disease (ALD), Parkinson’s disease (PAD) and amyotrophic lateral sclerosis (ALS). To capture data on early-stage disease, they collected stool samples from diagnosed patients within the first 2 visits to a specialist, and they compared analyses of those samples to samples collected from healthy controls. Their analysis revealed 19 metabolic biomarkers for neurodegeneration in all 3 NDD groups; they also found 20 unique ALS markers, 16 unique ALD markers and 9 unique PAD markers. Those shared biomarkers included metabolites that have been connected to dyshomeostasis in sulfur metabolism pathways. In addition, in all 3 disease groups, they found links to Desulfovibrio and Bilophila bacterial taxa, which play a role in synthesizing and degrading DHPS.
Those increased levels of Bilophila corresponded to the observation that patients with these three conditions had lower abundance of DHPS in stool samples, compared to healthy subjects. Bilophila can degrade DHPS into hydrogen sulfide, and the accumulation of hydrogen sulfide has been implicated in the dysfunction of mitochondria, which is known to contribute to NDDs. The cytoprotective effects of hydrogen sulfide signalling are now generally agreed to act predominantly via protein S-persulfidation, a process whereby the addition of a sulfur atom onto the thiol (-SH) adduct of a cysteine residue can alter its structure, stability and functional capacity post-translationally. Importantly, such cytoprotective effects of S-persulfidation have been shown for key mitochondrial defence proteins and subunits of the mitochondrial respiratory chain.
Thus, given the aberrant mitochondrial and protein dysfunction that occurs in primary mitochondrial diseases, mechanisms of sulfide signalling represent a fundamentally under-explored potential therapeutic role for disease treatment and modification of these conditions. Hydrogen sulfide is linked to inflammation, oxidative stress and gut dysbiosis. The occurrence of neurodegenerative phenotypes in mitochondriopathies are exceedingly common and typically result in death within the first few years of human life. Interestingly, hydrogen sulfide treatments have displayed direct modulation of proteins involved in both mitophagic and biogenesis pathways. Therefore, sulfur amonoacids (DHPS could well derive from cysteine bacterial metabolism) in microbiota could be an integral part of a complex mechanism by which human health is under the control of gut bacteria.
The authors suggested that the new study flags DHPS as a “missing link” in the current understanding of the mechanisms of how sulfur metabolism, mitochondria and neuroinflammation stay beneath neurodegenerative diseases. Same would go with inflammatory bowel disases, where genetic background and dietary choices intertwin to dictate the onset of these condition, where cellular metabolism is the “primum movens” of the incorrect dialogue between gut, its hosts and immune system.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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